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Colon-Targeted Delivery Systems for Therapeutic Applications: Drug Release from Multiparticulate, Monolithic Matrix, and Capsule-Filled Delivery Systems

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Colon-Targeted Delivery Systems for Therapeutic Applications: Drug Release from Multiparticulate, Monolithic Matrix, and Capsule-Filled Delivery Systems Chapter 13 Colon-Targeted Delivery Systems for Therapeutic Applications: Drug Release from Multiparticulate, Monolithic Matrix, and Capsule-Filled Delivery Systems Safa Cyrus Fassihi,1 Rahmat Talukder,2 and Reza Fassihi*,3 1George Washington University Hospital, 900 23rd Street NW, Washington, DC 20037, United States 2Department of Pharmaceutical Sciences, Fisch College of Pharmacy, The University of Texas at Tyler, 3900 University Boulevard, Tyler, Texas 75799, United States 3Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States *E-mail: [email protected]. Because of the relatively predictable times in which multiple unit-dosage forms transit the small intestine and arrive at the colon, targeted drug delivery systems are promising and have gained importance as a treatment for inflammatory bowel Downloaded via TEMPLE UNIV on March 20, 2019 at 18:49:47 (UTC). disease (IBD), as therapy for localized diseases of the colon, and as a potential means for the systemic delivery of drugs, proteins, and peptides. Enteric-coated or sustained-release tablets, capsules, liquid- and dispersion-filled softgel capsules, See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. encapsulated multiparticulates, pellets, beads, mini-tablets, granules, microspheres, and nanoparticle-type formulations have been developed to selectively deliver drugs to the target cells by resisting drug release in the upper intestine, thereby circumventing systemic side effects. Two different colon-targeted delivery systems, each with its own operating release mechanisms, have been designed and evaluated and are discussed in detail in this chapter. Technical aspects in development of each of the delivery systems, their coating composition, their manufacturing steps, and their release © 2019 American Chemical Society Sakurai and Ilies; Targeted Nanosystems for Therapeutic Applications: New Concepts, Dynamic Properties, Efficiency, and Toxicity ACS Symposium Series; American Chemical Society: Washington, DC, 2019. profiles are revealed. Based on the results, the developed delivery systems can overcome physiological barriers and target the colon for treating IBD. Encapsulation of multiparticulates, including nanoparticles or dispersed systems for colonic delivery, appears to be a promising approach in drug delivery to the colon. Furthermore, this chapter discusses peptide delivery and the use of a capsule device as a tool for research purposes in drug targeting to the gastrointestinal tract. Introduction For a drug delivery system to be effective and achieve success in pharmacotherapy, the intact drug must reach its target site or receptor to an extent that exceeds the minimum effective required concentration. To achieve this objective, the dynamic relationship between four key biopharmaceutical factors should be considered, as seen in Figure 1. These factors include the drug, the formulation, the route of administration, and the target response, the last of which encompasses both the pharmacokinetics and the pharmacodynamics of the drug. Figure 1. The quartet of rational drug delivery system design. The interrelationship and connection between four key factors: the drug, the formulation, biological aspects of the administration route, and the target site and response. Gastrointestinal drug targeting offers many key benefits to the successful pharmacotherapy of colonic inflammation and disease (1). In particular, site-specific delivery to the colon offers a means to achieve topical, localized, or systemic therapeutic effects, which is advantageous in addressing the mucosal redox status, persistent state of oxidative stress, and colon cancer (2, 3). For drug delivery to the distal intestine and colon, the utmost concern is how to trigger drug release selectively in the ileocecal region or the colon. Several release mechanisms can be used to accomplish this goal. For example, drug delivery systems based on pH-triggered release, time-triggered release, pressure-induced 310 Sakurai and Ilies; Targeted Nanosystems for Therapeutic Applications: New Concepts, Dynamic Properties, Efficiency, and Toxicity ACS Symposium Series; American Chemical Society: Washington, DC, 2019. shell rupture, and enzymatically triggered release for biodegradable polymers, azo-aromatic polymers, and prodrugs have been investigated (1, 4–6). Likewise, a new perspective on the oral delivery of peptides, proteins, and other labile drugs into the distal gastrointestinal (GI) tract and colon has been demonstrated (7, 8). The success of any delivery system and drug depends on the bioavailability of intact drug molecules at the target site of action, either topically or through systemic circulation. An ideal delivery system must release the drug at a specific rate that matches the real need in vivo. This means that the drug must be released for a certain duration of time and should be present exclusively at the target site of action or within a localized area, such as in certain localized cancers. Various drug delivery system domains and established manipulation techniques that are currently available and in use are presented in Figure 2. Figure 2. The domains of drug delivery systems including aspects of dispersed, personalized, biodegradable, microchip-based systems, three-dimensional (3D) printing dosages, sustained-release (SR) and enteric-coated (EC) tablets, capsules, pellets, gels, bioadhesive polymers and manipulated molecular structures and crystal engineered systems currently in use. Targeting in the GI Tract, Colon, and Mucosal Surfaces Depending on the site in the GI tract where a drug should be released, a variety of approaches and types of delivery systems are currently available and in use. An ideal dosage form for colon targeting should effectively delay or prevent drug release in the stomach and small intestine. However, upon arriving in the ileocecal region, the drug release should begin either rapidly or over an extended time period depending on the in vivo needs. The advantages of delivering a drug to the colon for topical effects include a reduction in the incidence of systemic side effects and 311 Sakurai and Ilies; Targeted Nanosystems for Therapeutic Applications: New Concepts, Dynamic Properties, Efficiency, and Toxicity ACS Symposium Series; American Chemical Society: Washington, DC, 2019. greater localized drug concentrations in the inflamed or diseased tissues (4, 7–10). Furthermore, in many cases, the drug dose can be reduced, as the drug is delivered directly in its intact form to the target site. For example, diseases such as ulcerative colitis, irritable bowel syndrome, and colon cancer can often be more efficiently treated while evading many systemic side effects through the local delivery of low doses of drugs (11, 12). Some of the drugs and prodrugs commonly used for the treatment of these disorders include mesalazine, budesonide, sulfasalazine, dexamethasone, hydrocortisone, metronidazole, prednisolone, cyclosporine, 5-florouracil, typhoid vaccines (e.g., enteric-coated oral capsules with live attenuated Ty21a), and peptides such as linaclotide and plecanatide. Moreover, conventional dosage forms such as enemas, rectal foams, and suppositories are used for the topical treatment of IBD, especially in anorectal regions including the sigmoid and descending colon. Prodrugs that are susceptible to reductive enzymes such as nitroreductases, azoreductases, and deaminases have been investigated extensively. For example, azo linkages resist proteolytic breakdown in the stomach and intestine but undergo reduction by azoreductases produced in the colon by indigenous microflora, with estimates indicating the presence of about 1012 colony-forming units (CFU) per gram of fecal matter (13). Figure 3 shows examples of commercially marketed prodrugs that are activated into 5-aminosalicylic acid by azoreductases occurring in the colonic environment. Figure 3. Sulfasalazine and olsalazine are effective in maintaining remission of ulcerative colitis. Through selective prodrug activation by azoreductases of anaerobic bacteria, 5-aminosalicylic acid is produced and can act to heal the local environment and reduce the number of relapses in colitis. Additionally, the colon’s neutral pH (7 ± 0.3), long residence time (>24 h), and relatively low proteolytic enzyme activity can be advantageous for delivering 312 Sakurai and Ilies; Targeted Nanosystems for Therapeutic Applications: New Concepts, Dynamic Properties, Efficiency, and Toxicity ACS Symposium Series; American Chemical Society: Washington, DC, 2019. drugs that are degraded or poorly absorbed in the upper gastrointestinal tract, such as peptides, protein-based drugs, calcitonin, and vasopressin (7, 14, 15). Moreover, drug delivery with particular release modulation (chronotherapy) for the treatment of certain diseases can be achieved by delivering drugs to the distal gastrointestinal environment (16). The major challenges of colonic drug delivery are related to the physiological constraints, as the gastrointestinal ecosystem is relatively complex (4). The presence of a variety of microorganisms and their enzyme systems is, in part, responsible for its metabolic diversity (13, 17, 18). As for many physiological parameters, gastrointestinal pH is influenced by various factors including diet; disease; and the presence of gases, fatty acids, and other fermentation products (19). In addition, gastric residence time
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